Air Pollution Ultrafine Particles: Toxicity Beyond the Lung

European Review for Medical and Pharmacological Sciences 2010; 14: 809-821 Air pollution ultrafine particles: toxicity beyond the lung

C. TERZANO, F. DI STEFANO, V. CONTI, E. GRAZIANI, A. PETROIANNI

Department of Cardiovascular and Respiratory Sciences, Respiratory Diseases Unit, Sapienza University of Rome, Fondazione E. Lorillard Spencer Cenci, Rome (Italy)

Abstract. – Background: Ultrafine parti- help in understanding not only the environmen- cles or nanoparticles (UFPs or PM0.1) are the tal mechanisms of disease, but also in develop- fraction of ambient particulates with an aerody- ing specific preventive or therapeutic strategies namic diameter smaller than 0.1 µm. for minimizing the dangerous influence of pollu- Currently UFPs are emerging as the most tion on health. abundant particulate pollutants in urban and industrial areas, as their exposures have in- Key Words: creased dramatically because of anthropogenic Nanoparticles, Lung injury, Cardiovascular disease, sources such as internal combustion engines, Health effects. power plants, incinerators and many other sources of thermo-degradation. Ultrafine particles have been less studied than PM2.5 and PM10 particulates, mass concentrations of particles smaller than 2.5 and 10 µm, respectively. Introduction Objective, Evidence and Information Sources: We examined the current scientific lit- The incidence and the prevalence of respirato- erature about the health effects of ultrafine parti- ry diseases have increased relentlessly along with cles exposure. air pollution and particulates are emerging as the State of the Art: UFPs are able to inhibit most dangerous pollutants for their adverse phagocytosis, and to stimulate inflammatory re- health effects going far beyond the simple toxici- sponses, damaging epithelial cells and poten- 1 tially gaining access to the interstitium. They ty to the lung . could be responsible for consistent reductions Particulates are a mixture of solid and liquid in forced expiratory volume in 1 second (FEV1) tiny particles in the air of different origin, size and forced vital capacity (FVC) in patients with and composition: various classifications and ter- asthma. Chronic exposure to UFPs can produce minologies have been used to define particle size deleterious effects on the lung, also causing ox- ranges. The division most commonly used is be- idative stress and enhancing pro-inflammatory effects in airways of COPD patients. tween fine and coarse particles, with the bound- Cardiovascular detrimental consequences ary between these two fractions being widely ac- due to UFPs exposure have observed in epi- cepted as 2.5 µm. Fine particles are smaller than demiological studies, and could likely be ex- this and coarse particles are larger. plained by translocation of UFPs from the respi- The terminology that has been used in the ratory epithelium towards circulation and subse- wording of the ambient air quality standards, and quent toxicity to vascular endothelium; alter- also for characterization of indoor and outdoor ation of blood coagulation; triggering of autonomic nervous system reflexes eventually alter- particle mass concentrations includes the PM2.5 ing the cardiac frequency and function. and PM10 fractions. PM2.5 (fine particles) is the Once deposited deeply into the lung, UFPs – mass concentration of particles with aerodynam- in contrast to larger-sized particles – appear to ic diameters smaller than 2.5 µm. PM10 (coarse access to the blood circulation by different particles) is the mass concentration of particles transfer routes and mechanisms, resulting in with aerodynamic diameters smaller than 10 µm. distribution throughout the body, including the brain, with potential neurotoxic consequences. In most urban and industrial environments both Perspectives and Conclusions. UFPs repre- coarse and fine particles are likely to be promi- sent an area of toxicology of emerging concern. nent, the former primarily derived by construc- A new concept of environmental medicine would tion and demolition activities, mining and caving

Corresponding Author: Claudio Terzano, MD; e-mail: [email protected] 809 C. Terzano, F. Di Stefano, V. Conti, E. Graziani, A. Petroianni operations, and entrainment of road dust into the and with lung cancer2-9. It has been also demon- air, the latter primarily produced by combustion strated a strong evidence of a relation between of fossil fuels from power plants and vehicles. PM2.5 and hospitalizations for both respiratory Ambient particles include also ultrafine parti- and cardiovascular diseases10,11. cles or nanoparticles (UFPs or PM0.1) which have Additionally, exposure to PM2.5 is associated an aerodynamic diameter smaller than 0.1 µm. with increased daily mortality for all-causes and Another classification is into submicrometre for single subgroups, including respiratory dis- particles, which are smaller than 1 µm, and su- eases, cardiovascular diseases, diabetes12. permicrometre particles, which are larger than 1 Two large cohort studies in the USA, the Six µm. City Study2 and the American Cancer Society There have been references made in the litera- study3, showed highly significant associations of ture to PM1 or PM0.1 fractions, which imply mass all-cause and cardiopulmonary mortality rates concentrations of particles smaller than 1 and 0.1 with increasing levels of fine particles. Results of micrometres, respectively. These terms should be these two studies were so relevant that led the used with caution, as particles below 1 microme- Environment Protection Agency to place regula- tre, and, even more importantly, those below 0.1 tory limits on PM2.5 and revise the National Am- micrometres, are more commonly measured in bient Air Quality Standards. The risk for various terms of their number rather than their mass con- outcomes has been shown to increase with expo- centration. In fact, since ultrafine particles reach sure, but so far epidemiological evidences do not high concentrations in terms of their numbers but suggest a threshold below which any adverse their mass is often very small, measurements of health effects would be avoided. particles in ultrafine or broader, submicrometre In fact, the lower range of concentrations at ranges are more commonly based on particle which adverse health effects have been demon- number rather than mass concentration. Further- strated is not greatly above the background con- more, the ultrafine particle size range tends to centration in urban areas. The European Respira- dominate particle number size distribution tory Society13 has published recently its concern whereas the coarse particle size range tends to about the mismatch between European Union dominate the particle mass size distribution. policy and the best scientific evidence on adverse Generally UFPs are combustion derived, such health effects of particulates, stating that imple- as diesel exhaust particles. Their chemistry is de- menting stringent air pollution legislation would rived from the combustion and pyrolysis process- result in life expectancy gains and pointing out es, whereby combustion concentrates transition that the benefits would outweigh the costs. metals and pyrolysis generates organic com- A recent study has directly evaluated the pounds, along with elemental organic carbon par- changes in life expectancy associated with differ- ticles. The chemical composition of UFPs varies ential changes in fine particulate air pollution greatly and depends on numerous geographical, that occurred in the United States during the meteorological, and source-specific variables, in- 1980s and 1990s14, demonstrating that a reduc- cluding inorganic components (sulfates, nitrates, tion in exposure to PM2.5 contributed to signifi- ammonium, chloride, trace metals), elemental and cant and measurable improvements in life ex- organic carbon, crystal materials, biological com- pectancy. ponents (bacteria, spores, pollens), and adsorbed Ultrafine particles have been less studied than volatile and semivolatile organic compounds. In PM2.5 and PM10 particulates. Relatively few epi- addition, ambient particles, when mixed with at- demiologic studies have examined the health ef- mospheric gases (ozone, sulfur and nitric oxides, fects of ultrafine particles exposure because most and carbon monoxide [CO]), can generate ambient ambient air monitoring measures particle mass, aerosols. Currently ultrafine particles are emerging and there is relatively poor correlation between as the most abundant particulate pollutants in ur- particle mass (dominated by PM10 and PM2.5) and ban and industrial areas, as their exposures have particle number (dominated by UFPs). It has increased dramatically because of anthropogenic been showed that the smaller the size of the parti- sources such as internal combustion engines, pow- cles the more dangerous the health effects4 and er plants, incinerators and many other sources of ambient UFPs concentrations have been clearly thermo-degradation. associated with mortality15 (Figure 1).

Fine particulates (PM2.5) have been associated Compared with fine particles at similar mass with both respiratory and cardiovascular diseases concentrations in the air, UFPs have a much high-

810 Air pollution ultrafine particles: toxicity beyond the lung

Figure 1. Systemic health effects of UFPs. er number concentration and surface area than transcription factors (i.e., mitogen-activated pro- larger particles16, enhanced oxidant capacity17,18, tein kinase and nuclear factor-κB25,26. Consider- greater inflammatory potential16 and higher pul- ing particles in the ultrafine size range, lung in- monary deposition efficiency19,20. flammation is a consequence not of the mass, but The UFPs are not filtered out by the nose and of the number of particles27. The respiratory tract bronchioles and their size allows them to be is subjected to daily low mass concentrations of breathed deeply into the lungs where they are particles, but high number concentrations27,28. able to penetrate alveolar epithelium and enter It is estimated that on a so-called “low pollu- the pulmonary interstitium and vascular space to tion” day (over 24 h), an adult human will inhale be absorbed directly into the blood stream21. approximately 200 billion particles, half of The body does not have efficient mechanisms which will be deposited in the lung, without ap- for clearing the deeper part of the lung as only a parent harm27. These huge numbers of particles tiny fraction of natural particles will be as small are contained in a very small mass (400 µg). as this. The UFPs are highly chemically reactive During pollution episodes, where the average due to property of their small size and large sur- particle mass rises to 50 µg/m3, the mass of in- face area22, as surface molecules depend on the haled particles associated with adverse respirato- particle size, increasing exponentially when par- ry effects may contain 2000 billion particles27. ticle size decreases <0.1 µm. Moreover, they car- Although the physicochemical properties differ ry large amounts of toxic compounds on their greatly among different types of UFPs, they have surfaces23. For example, in incinerators air emis- a soluble component and release transition met- sions, heavy metals, dioxins, hydrocarbons and als or organics as their primary pro-inflammatory other organic chemicals can adhere to UFPs sur- mechanisms. When the transition metals and face and increase their toxicity24. polycyclic aromatic hydrocarbons (PAHs) interact with the lining fluids of the lung, they under- Pulmonary Toxicity go cycling redox reactions that produce reactive Inhalation of UFPs causes inflammation via oxygen species (ROS) (e.g., superoxide anions, oxidative stress and activation of redox-sensitive hydroxyl radicals)27.

811 C. Terzano, F. Di Stefano, V. Conti, E. Graziani, A. Petroianni

Carbon particles derived from combustion asthma prevalence and airway hyper-reactivity in processes are the most numerous particles in the response to elevated levels of ambient particulate ultrafine range. Carbon particles aggregate easily matter47,48. into clusters containing substances like iron, oth- The combination of mucosal stimulation with er transition metals, volatile organic compounds diesel exhaust particles (DEP) and ragweed aller- and polycyclic aromatic hydrocarbons, which all gen was shown to be capable of driving in vivo have been associated with the inflammatory reac- isotype switching to IgE in humans with ragweed tion caused by particles29-33. allergy49. These results further support the con- Independently of their chemical composition, cept that increasing environmental DEP with un- the inflammatory properties of ultrafine parti- changed levels of allergen could be a factor in the cles are mediated by their large numbers, small increasing clinical sensitization. It is also possi- size and high penetration rate into the intersti- ble that DEP may not only enhance isotype tium34, as they are not readily and easily phago- switching and IgE production but, in conjunction cytized by alveolar macrophages35. UFPs have with an antigen, it may also help to induce a de a deleterious effect on phagocytosis of alveolar novo specific IgE mucosal response. Experimen- macrophages36. The effect is not apparently metal data show that exposure to ultrafine carbon diated by soluble mediators but by ultrafine particles before allergen challenge exerts strong particle cell contact, which rapidly stimulate adjuvant effects on the elicitation phase of the al- the opening of membrane calcium channels in lergic response50,51. Allergen’ sensitized subjects macrophages, leading to a substantial increase may therefore be more susceptible to adverse res- in the intracellular calcium levels37-39. The role piratory health effects of ultrafine particles. that these calcium fluxes play in the inhibition Cronic exposure to UFPs can produce deleteri- of phagocytosis needs more investigations, but ous effects on the lung leading to chronic ob- increased calcium stimulates transcription of structive pulmonary disease (COPD)52. Ultrafine pro-inflammatory genes in macrophages as particles and transition metals they carry on their well as in epithelial cells40. Thus the adverse ef- surface cause oxidative stress and this may en- fects of ultrafine particles may be mediated in hance pro-inflammatory effects in airways of part by their ability to inhibit phagocytosis, al- COPD patients. The generation of oxidative stress lowing ultrafine particles and other particles directly from the ultrafine and transition metal that deposit along with them to persist un- component of particulates and indirectly from the phagocytosed in the lung, and stimulating in- recruitment to the airspaces and activation of flammatory responses, damaging epithelial blood leukocytes, could enhance the already in- cells and potentially gaining access to the inter- creased oxidant burden which occurs in the lungs stitium. of patients with COPD53 and cause transcription Recently it has been observed that the expo- of pro-inflammatory genes via redox sensitive sure to the diesel traffic is responsible for a con- transcription factors, such as nuclear factor kappa sistent reduction in forced expiratory volume in 1 B (NF-B) activation and histone acetylation54.In- second (FEV1) and forced vital capacity (FVC) fection with virus and other pathogens may also in persons with asthma41. interact with oxidative stress to promote exacer- It has been suggested that the high number of bations, as alveolar epithelial cells upregulate IL- particles below 0.1 µm in diameter (UFPs) may 8 messenger ribonucleic acid (mRNA) and re- be responsible for the adverse respiratory effects lease increased IL-8 protein in response to parti- of particulate air pollution and be more strongly cles55. associated with decrease in lung function in asth- A recent study suggests that elevated concen- matic patients42-44. In asthmatic patients UFPs trations of air pollution are associated with were associated with a decrease in peak expirato- changes in some blood markers of inflammation ry flow and increase in self-reported symptoms43, and coagulation (e.g., fibrinogen, E-selectin ) in daily variations of PEF45, asthma medication use patients with COPD56. and symptoms46. Patients with obstructive lung disease have a There is increasing evidence that ultrafine par- higher minute ventilation than healthy people, ticulate pollutants exert adverse pulmonary ef- because of increased dead space ventilation. The fects by generating airway inflammation as well increased minute ventilation and hyperinflation as acting as adjuvants for IgE production in the that are characteristic of COPD and even mild immune system47,48, explaining the increased asthma, enhance diffusional deposition of UFPs

812 Air pollution ultrafine particles: toxicity beyond the lung in the distal airways and alveoli57-59. Thus, people In a recent work ultrafine particle-exposed with COPD and asthma have a higher total respi- mice exhibited significantly larger early athero- ratory dose of UFPs for a given exposure, which sclerotic lesions than mice exposed to PM2.5 or may contribute to their increased susceptibility to filtered air83. Exposure to ultrafine particles also the health effects of air pollution. resulted in an inhibition of the antiinflammatory Numerous epidemiological studies in the past capacity of plasma high-density lipoprotein and 30 years found a strong exposure-response rela- greater systemic oxidative stress as evidenced by tionship between particulates and long-term or a significant increase in hepatic malondialdehyde cumulative health effects as lung cancer, together levels and upregulation of Nrf2-regulated antiox- with cardiopulmonary morbidity and mortality60. idant genes83. These effects are stronger for fine and ultrafine In a recent investigation, the Exposure and particles because they can penetrate deeper into Risk Assessment for Fine and Ultrafine Particles the airways of the respiratory tract and can reach in Ambient Air or so called ULTRA study84, Au- the alveoli in which almost 50% are retained in thors followed a cohort of patients with estab- the lung parenchyma, where exert genotoxicity lished coronary heart disease with biweekly sub- and carcinogenic mechanisms61-63. maximal exercise tests over a 6-months period. The process involved in particle-induced geno- They observed that the risk of developing is- toxicity remains poorly understood, because the chemia during exercise was significantly elevated particles are uniquely complex owing to their at 2 days after exposure to increased environmen- physicochemical characteristics. There is evi- tal levels of fine particulate air pollution, with the 64 dence that diesel exaust particles (DEP) , carbon strongest effects for PM0.1 and PM2.5. The impor- blacks particles (CB)65, and coal fly-ash (FA)66 tance of this observation is that it highlights my- are carcinogenic in humans. DEP consist of a ocardial ischemia as a significant potential mech- carbon core with adsorbed polycyclic aromatic anism responsible for the adverse cardiac out- hydrocarbons (PAHs) and transition metals67. comes associated with poor air quality. It remains Genotoxicity may be induced by the direct inter- unclear whether ischemia contributes to the ad- action of PAHs, which are known to cause DNA verse cardiac outcomes observed in epidemiolog- adducts68,69. Alternatively, the transition metals ical studies through a mechanism related to may induce ROS, which results in DNA strand plaque rupture leading to an acute coronary syn- breakage70. Carbon black is generally devoid of drome and/or to precipitation of life-threatening adsorbed organics and metals and, thus, its geno- arrhythmias. toxicity is most likely an effect of the particle Recently in has been observed an increase in overload phenomenon, but some research has re- plasma soluble CD40ligand (sCD40L, also vealed the formation of the oxidative DNA lesion known as CD154, a marker for platelet activation 8-hydroxydeoxyguanosine (8-OH-dG)65,71. Stud- that can cause increased coagulation and inflam- ies investigating the genotoxicity of FA have de- mation) and a reduction in platelet counts, in as- termined a role for particle size and iron release sociation with exposure to ultrafine particles, in leading to radical generation and oxidative patients with coronary heart disease (CHD)85. stress72. The increased plasma sCD40L levels support the hypothesis that higher levels of ambient air pol- Cardiovascular Toxicity lution lead to an inflammatory response in pa- Epidemiologic studies have demonstrated that tients with CHD thus providing a possible expla- exposure to particulate air pollution is an impor- nation for the observed association between air tant risk factor in the development of cardiovas- pollution and cardiovascular morbidity and mor- cular disease73-75. Several important cardiovascu- tality in susceptible parts of the population85. lar effects have been documented, including dis- The ULTRA study focused on patients with ruption of autonomic nervous system activity by known cardiac disease, but it would also be im- decreased heart rate variability76,77, arterial vaso- portant to determine whether other patient popu- constriction78, cardiac arrhythmias in patients lations are also susceptible to poor air quality, with implantable defibrillators79, myocardial in- such as those with diabetes86 or pulmonary dis- farction80 and other cardiac events requiring hos- ease. An increase in stroke mortality among the pitalization81, and exacerbation of ST-segment elderly in association with daily variations in changes in experimental models of myocardial PM2.5, and to a lesser extent with ultrafine parti- infarction82. cles and CO has been found87-89.

813 C. Terzano, F. Di Stefano, V. Conti, E. Graziani, A. Petroianni

Nanoparticles have a diameter of less than 0.1 lymphatics. UFPs could also be cleared in the µm, and while constituting a small fraction of the alveolar region by alveolar macrophages, through total mass of ambient particulate matter, they rep- phagocytosis of deposited particles followed by resent a substantial proportion in terms of particle gradual movement of the macrophages with in- number. Toxicologists suggest that the nanopar- ternalized particles toward the mucociliary sys- ticulate component of ambient particulate matter tem. However due to difference in primary parti- is the most potent and likely to be responsible for cles size and to degree of particles aggregation, adverse cardiovascular health effects90. UFPs may escape phagocytosis, or the cascade of The precise mechanism by which air pollution events leading to alveolar macrophage-mediated influences cardiovascular risk has not been fully clearance may be more or less effective. The ra- understood yet. However, a number of interesting pidity of lung clearance101,102 makes it unlikely hypotheses have been proposed to explain how that phagocytosis by macrophages and/or tran- inhaled particles could interact with the cardio- scytosis across epithelial and endothelial cells vascular system73,85,91. The traditional view is that are exclusively responsible for particle-translo- inhaled particles provoke an inflammatory re- cation to the blood102, as there is experimental sponse in the lungs, with consequent release of evidence suggesting the existence of functional prothrombotic and inflammatory cytokines into pores in the alveolar-blood barrier103, through the circulation, which can affect the stability of which UFPs may go directly in the blood, simi- the atheromatus plaques (fatty deposits) in the larly to lung epithelial specific proteins104. Alter- walls of arteries92-94. These compounds may then natively, a slower active transfer of particles trigger a cascade of reactions: initial local pro- from the lung into the circulation could explain a duction by macrophages and activated alveolar recent finding that the majority of 99mTc-labeled cells of pro-inflammatory cytokines, such as in- carbon nanoparticles remains within the lung up terleukin-695, and increased expression of en- to 6 h after inhalation in humans105; in this case dothelin96, whose elevated systemic levels are as- the traslocation may be intracellular due to sociated with a poor cardiovascular prognosis97. phagocytosis of particulate in the lung alveolar This induced systemic inflammation may be re- space or interstitium by cells of the monocyte/ flected by elevated C Reactive Protein (CRP)98 macrophage lineage, which then enter the circu- which is significantly and independently associ- lation105. The circulating particles may interact ated with the risk of coronary heart disease95,99. with vascular endothelium/atherosclerotic le- Other studies have shown increased levels of fib- sions, causing local oxidative stress that could rinogen and platelets100, altered blood viscosity78, destabilize plaques, setting off a chain reaction modification of the adhesive properties of red (rupture, thrombosis) with resultant acute car- blood cells with peripheral sequestration, and al- diovascular events (acute coronary syndrome tered vascular tone78. and stroke)102,106. Furthermore, particles may in- Recent evidences suggest also that inhaled interact with circulating coagulation factors to pro- soluble nanoparticles may be capable of rapid mote thrombogenesis106,107. The UFPs/NPs could translocation into the circulation, with the poten- also have effects on cardiac physiology if they tial for direct effects on cardiovascular integri- act directly or perhaps as a result of a local in- ty101-103. Experimental studies investigating the flammatory response, on nerve endings in the traslocation of inhaled UFPs into the blood cir- walls of the airways throughout the respiratory culation showed in hamsters the rapid clearance system. Activation of such receptors initiates of instilled albumin nanoparticles from the lungs changes in the autonomic control of the heart to the bloodstream (25-30% in 5 minutes)101;in and, thus, changes in the heart’s rhythm (e.g. fa- humans, after inhaling 99mTc-labeled carbon tal arrhythmias)76,77,79,108. Environmental combus- nanoparticles, it could be observed the rapid ap- tion-derived nanoparticulate, as a carrier of solu- pearance of the radioactive label in the blood ble organic compounds from unburned hydro- followed by the significant accumulation in the carbon fuels109 and oxidized transition metals109, liver102. may well exert an important influence on the The exact mechanism for this translocation re- cardiovascular system. They contain a high con- mains to be established. UFPs could be involved tent of redox-cycling organic chemicals that not in a transcytosis across epithelia of the respirato- only could be released deep into the lungs but ry tract into the interstitium and then they gain also could even spill over into the systemic cir- access to the blood circulation directly or via culation109,110.

814 Air pollution ultrafine particles: toxicity beyond the lung

Potential other Target Tissues Toxicity Recent experimental evidences in animals in- As explained previously, once deposited dicate traslocation of UFPs to ganglionic and deeply into the lung, UFPs – in contrast to larger- central nervous system structures trough a mech- sized particles – appear to access to the blood anism that involves their uptake by sensory nerve circulation by different transfer routes and mech- endings embedded in airway epithelia, followed anisms, resulting in distribution throughout the by axonal transport115. body. The liver is the major distribution site via In experimental animal models translocation uptake by Kupffer cells, followed by the spleen of UFPs to the central nervous system has also and bone marrow as other organs of the reticulo- been described trough a mechanism involving the endothelial system111. Through an innovative olfactory bulbs and the olfactory nerve, as the electron microscopy technique, the presence of close proximity of nasal olfactory mucosa and nano-sized inorganic, neither biodegradable nor olfactory bulb requires only a short distance to be biocompatible particles were found in thrombi covered by neuronal transport116,117. Collectively, and fibrotic tissue taken from explanted vena ca- these studies point out that under conditions of va filters in patients with blood coagulation dis- environmental and occupational exposures of hu- orders and recurrent pulmonary embolism112,113. mans to airborne UFPs, the airway sensory nerve UFPs did not belong to the metal the device was and the olfactory nerve pathways should also be made of, probably deriving from pollutant considered a portal of entry of UFPs to the cen- sources, as the chemistry of these particles was tral nervous system, but confirmatory studies are different and varied, and unusual compounds necessary. containing non-biocompatible elements like bis- Indirect evidence for movement of UFPs along muth, lead, tungsten were detected. They fre- axons and dendrites in humans is provided by quently activated immunological reactions typi- knowledge accumulated by virologists who have cal of a foreign body. The interaction between long understood the movement of human menin- these UFPs traveling in the blood stream and the gitis virus through olfactory and trigeminal neu- blood itself might leads to suspect that the forma- rons and, similarly, herpes virus movement up tion of the thrombus can originate from these in- and down the trigeminal neuron to trigger out- organic and inert nanosized particles that act as breaks of herpes cold sores in humans118,119. triggering factors of the blood coagulation112,113. In the context of potential central nervous sys- Once accessed the blood circulation, UFPs are tem effects of air pollution UFPs, a recent study so translocated to other organs including the liver, with exposures of mice to concentrated ambient the spleen, the kidneys, the heart and the brain, fine particles and UFPs found significant increases where they may be deposited114. There is the poten- of tumor necrosis factor-α (TNF-α) or decreases in tial for neurodegenerative consequence of particle dopaminergic neurons, supporting the hypothesis entry to the brain. Histological evidence of neu- of ambient particulates causing neuro-degenerative rodegeneration has been reported in both canine disease120. An other study described significant in- and human brains exposed to high ambient PM flammatory or neurodegenerative changes in the levels, suggesting the potential for neurotoxic con- olfactory mucosa, olfactory bulb, and cortical and sequences of PM entry114. PM mediated damage subcortical brain structures in dogs from a particu- may be caused by the oxidative stress pathway. lates heavily polluted area in Mexico City, whereas Thus, oxidative stress due to nutrition, age, genet- these changes were not seen in dogs from a less- ics among others may increase the susceptibility polluted rural control city121. However, whether di- for neurodegenerative diseases114. The relationship rect effects of airborne UFPs were the cause of between PM exposure and central nervous system these central nervous system consequences re- (CNS) degeneration can also be detected under mains to be determined. Moreover, evidences of controlled experimental conditions114. Transgenic neurologic pathologies due to the presence of UF- mice (Apo E -/-), known to have high base line lev- Ps in the human CNS are to date still lacking. els of oxidative stress, were exposed by inhalation to well characterized, concentrated ambient air pollution. Morphometric analysis of the CNS indicat- ed unequivocally that the brain is a critical target Discussion for PM exposure and implicated oxidative stress as a predisposing factor that links PM exposure and Epidemiological studies indicate associations susceptibility to neurodegeneration114. between exposure to ambient UFPs and adverse

815 C. Terzano, F. Di Stefano, V. Conti, E. Graziani, A. Petroianni health effects. The lung is the primary target of would help in understanding not only the envi- UFPs, but also their portal of entry into the hu- ronmental mechanisms of disease, but also in de- man body with the cardiovascular system emerg- veloping specific preventive or therapeutic strate- ing as the final most sensitive target. Cardiovas- gies for minimizing the dangerous influence of cular detrimental consequences due to UFPs ex- pollution on health. posure have been observed in epidemiological studies, and could likely be explained by translocation of UFPs from the respiratory epithelium towards circulation and subsequent toxicity to vascular endothelium; alteration of blood coagu- References lation; triggering of autonomic nervous system reflexes eventually altering the cardiac frequency 1) WORLD HEALTH ORGANIZATION. WHO Air Quality and function. Respiratory and cardiovascular tis- Guidelines, global update 2005. Report on a sues are highly vulnerable to UFPs exposure, Working Group meeting, Bonn, Germany, 2005. which should be recognized as a cardiopul- 2) DOCKERY DW, POPE CA 3RD, XU X, SPENGLER JD, monary hazard. Respiratory and cardiovascular WARE JH, FAY ME, FERRIS BG JR, SPEIZER FE. An as- disease risk factors, endemic in industrialized so- sociation between air pollution and mortality in cieties, are likely influenced by environmental six U.S. cities. N Engl J Med 1993; 329: 1753- exposure to harmful chemicals and pollutants. 1759. Neurological consequences of UFPs have been 3) POPE CA 3RD, THUN MJ, NAMBOODIRI MM, DOCKERY showed in experimental animal models, but little DW, EVANS JS, SPEIZER FE, HEATH CW Jr. Particulate air pollution as a predictor of mortality in a is known in humans. The environmental context prospective study of US adults. Am J Respir Crit within which a pathophysiological process takes Care Med 1995; 151: 669-674. place should be studied as closely and rigorously 4) DE HARTOG JJ, HOEK G, PETERS A, TIMONEN KL, IBALD- as the biochemical mechanism of the pathologi- MULLI A, BRUNEKREEF B, HEINRICH J, TIITTANEN P, VAN cal process. At present, most investigators ad- WIJNEN JH, KREYLING W, K ULMALA M, PEKKANEN J. Ef- dress only disease biochemical mechanisms that fects of fine and ultrafine particles on cardiorespi- contribute to disease development and individual ratory symptoms in elderly subjects with coronary heart disease: the ULTRA Study. Am J Epidemiol susceptibility genes, while genes/environment in- 2003; 157: 613-623. teraction are considered less relevantly in the disease generating pathological process. The envi- 5) GOLDBERG MS, BURNETT RT, BAILAR JC 3RD, BROOK J, BONVALOT Y, T AMBLYN R, SINGH R, VALOIS MF, VINCENT ronment could induce complex genetic alter- R. The association between daily mortality and ations due to the plasticity of the genome which ambient air particle pollution in Montreal, Quebec. might react to thousands of pollutants122. These 2. Cause-specific mortality. Environ Res 2001; 86: alterations could persist in succeeding genera- 26-36. 122 tions through epigenetic and genetic changes . 6) POPE CA 3RD, BURNETT RT, THUN MJ, CALLE EE, Experimental data show that male mice exposed KREWSKI D, ITO K, THURSTON GD. Lung cancer, car- to ambient air near an urban industrial site in diopulmonary mortality, and long-term exposure 123 to fine particulate air pollution. JAMA 2002; 287: Canada showed a 1.5- to 2-fold increase in 1132-1141. germline mutation rate and that removal of particulate air pollution reduced heritable mutation 7) HOEK G, BRUNEKREEF B, FISCHER P, VAN WIJNEN J. The 124 association between air pollution and heart fail- rates at repetitive DNA loci pollutants . Al- ure, arrhythmia, embolism, thrombosis and other though pollutant-induced inheritable changes cardiovascular causes of death in a time series. have not been demonstrated in humans, increased Epidemiology 2001; 12: 355-357. episodic air pollution have been linked to in- 8) GOLDBERG MS, BURNETT RT, BAILAR JC 3RD, TAMBLYN 125 creased DNA fragmentation in human sperm R, ERNST P, F LEGEL K, BROOK J, BONVALOT Y, S INGH R, UFPs represent an area of toxicology of VALOIS MF, VINCENT R. Identification of persons with emerging concern. A multidisciplinary approach cardiorespiratory conditions who are at risk of dy- ing from the acute effects of ambient air particles. including atmospheric scientist, nanomaterial en- Environ Health Perspect 2001; 109(Supp 4): 487- gineers, epidemiologists, clinicians and toxicolo- 494. gists is necessary to investigate UFPs sources, 9) SAMET JM, DOMINICI F, C URRIERO FC, COURSAC I, ZEGER generation, physicochemical characteristics and SL. Fine particulate air pollution and mortality in potential harmful effects following their inhala- 20 US cities 1987-1994. N Engl J Med 2000; 343: tion. A new concept of environmental medicine 1742-1749.

816 Air pollution ultrafine particles: toxicity beyond the lung

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